4GR0

Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470B

4GR0 の概要

• エントリーDOI: 10.2210/pdb4gr0/pdb
• 関連するPDBエントリー: 3LIK 3LIL 3LIR 3LJG 3TS4 3TSK 4EFS 4GQL 4GR3 4GR8
• 関連するBIRD辞書のPRD_ID: PRD_000865
• 分子名称: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: potent selective phosphinic inhibitor, metzincin, zinc protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space, extracellular matrix (Probable): P39900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18568.65

構造登録者

Stura, E.A.,Vera, L.,Beau, F.,Devel, L.,Cassar-Lajeunesse, E.,Dive, V. (登録日: 2012-08-24, 公開日: 2013-02-06, 最終更新日: 2023-09-13)

主引用文献

Czarny, B.,Stura, E.A.,Devel, L.,Vera, L.,Cassar-Lajeunesse, E.,Beau, F.,Calderone, V.,Fragai, M.,Luchinat, C.,Dive, V.
Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies.
J.Med.Chem., 56:1149-1159, 2013

PubMed Abstract: The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor toward matrix metalloprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography, and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 Å) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P(1)' side chain filling most of the S(1)' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (ΔG° = -13.1 kcal/mol, ΔH° = -2.53 kcal/mol, and -TΔS° = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor while maintaining high affinity.

PubMed: 23343195
DOI: 10.1021/jm301574d

実験手法

X-RAY DIFFRACTION (1.497 Å)